Process

ABSTRACT

The present invention provides an improved process for the preparation of α-polymorphic eletriptan hydrobromide.

This application is a United States utility application, which claimsthe benefit of priority to United Kingdom application Serial No.0317229.3 filed Jul. 23, 2003 and U.S. provisional application Ser. No.60/511,182 filed Oct. 14, 2003.

The present invention relates to an improved process for the preparationof the α-polymorphic crystalline form of eletriptan hydrobromide.

Eletriptan,3-{[1-methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulfonylethyl)-1H-indole,and a process for its preparation, are disclosed in U.S. Pat. No.5,607,951. Further processes for the preparation of eletriptan aredisclosed in EP-B-1088817 and WO-A-02/50063.

Eletriptan hydrobromide has the structure of formula (I) below.

WO-A-96/06842 discloses eletriptan hydrobromide, two of its crystallineforms and processes for the preparation thereof. One of the crystallineforms disclosed therein, designated the α-form, is currently marketed asa treatment for migraine under the name Relpax™.

WO-A-00/32589 discloses a crystalline monohydrate of eletriptanhydrobromide and processes for its preparation.

Two processes for the conversion of eletriptan free base to theα-polymorph of eletriptan hydrobromide are disclosed in WO-A-96/06842.According to the first process, a solution of eletriptan in acetone istreated with an aqueous solution of hydrogen bromide and the resultingoil is crystallised from 2-propanol. According to the second process, asolution of eletriptan in acetone is treated with an aqueous solution ofhydrogen bromide and the reaction mixture is slurried, heated at reflux,cooled and slurried a second time.

Under large scale conditions, the yield of eletriptan hydrobromide usingthese prior art processes is in the region of 73%.

It will be appreciated that in the preparation of sufficient quantitiesof eletriptan hydrobromide to satisfy the global market for Relpax™,increases in yield, particularly in a late-stage step of the commercialprocess, are extremely significant in reducing the cost of drug productand are consequently of high commercial importance. Any successfulprocess must also be robust in the sense of reliably producing ahomogeneous product containing the same crystalline form, free of othercrystalline forms and solvates.

It has now been surprisingly found that a high yielding and robustprocess for the preparation of the α-polymorph of eletriptanhydrobromide is provided by (a) treating a solution of eletriptan in2-butanone with hydrobromic acid and (b) distilling off a2-butanone/water azeotrope until formation of anhydrous α-polymorphiceletriptan hydrobromide is complete.

The yield obtained when using this process on a large scale is in theregion of 93 to 96%. The product obtained is exclusively the α-polymorphof eletriptan hydrobromide; no other polymorphic forms or solvates havebeen observed. Advantageously, the product obtained has a desirablewhite colouration.

The product of step (a) is thought to be a hydrate, probably themonohydrate described in WO-A-00/32589. This hydrate is then convertedin step (b) to form the desired product.

The eletriptan starting material is preferably dry (less than 0.3% waterby Karl Fisher analysis) and free of particulate impurities (thesolution in 2-butanone can be filtered if necessary). The hydrobromicacid is preferably a 48% aqueous solution and is advantageously added tothe reaction vessel as a solution in 2-butanone, over a period of atleast an hour and at room temperature. This form of addition ensuresthat the pH of the reaction mixture does not fall below 5 and leads to acleaner reaction and a higher yield. The use of from 0.95 to 1.05 molarequivalents of hydrobromic acid is preferred, the use of 0.98 molarequivalents being optimal. About 21 litres of 2-butanone per kilogram ofeletriptan starting material should preferably be used in total. Afteraddition of the hydrobromic acid, the reaction is stirred, preferablyfor a period of at least 3 hours.

During the azeotropic distillation, substantially all the water shouldbe removed from the reaction mixture. A final water content of less than0.5% weight/weight is preferred. Where about 21 litres of 2-butanone perkilogram of eletriptan starting material has been used in conjunctionwith 0.98 equivalents of 48% hydrobromic acid, a final volume of about11 litres per kilogram of eletriptan is ideal.

The product is conveniently isolated by filtration. Typically, thereaction mixture is allowed to cool slowly to room temperature,optionally granulated, filtered, washed with further 2-butanone anddried.

The α-polymorphic eletriptan hydrobromide prepared by the above processmay optionally be subjected to a further processing step, known as apolymorph annealing step, which increases its resistance to subsequenthydration. Thus, according to optional step (c), the product of step (b)is slurried in refluxing toluene and a proportion of the toluene isremoved by distillation. Preferably, at least 12% of the toluene isremoved; most preferably about 16.5% is removed. Step (c) may beoptionally repeated.

An initial volume of 15 litres of toluene per kilogram of eletriptanhydrobomide is preferred. For optimal results, the distillation oftoluene should be repeated twice and the reaction mixture should beheated at a sub-reflux temperature for a minimum of two hours in betweenthe distillations. A sub-reflux temperature of about 106° C. is ideal.

The final product is conveniently isolated by filtration. Typically, thereaction mixture is cooled to room temperature, granulated, filtered,washed with further toluene and dried.

Step (c) is advantageously carried out under an atmosphere of nitrogento prevent discolouration of the product.

A further embodiment of the invention provides a process for generatingstable α-polymorphic eletriptan hydrobromide from any other polymorphicand/or solvated/hydrated form of eletriptan hydrobromide or from amixture of different polymorphic and/or solvated/hydrated forms(including a mixture comprising the α-polymeric form itself).

This conversion process comprises the steps of (a) crystallising asolution of the eletriptan hydrobromide starting material in a mixtureof 2-butanone and water and (b) distilling off a 2-butanone/waterazeotrope until formation of anhydrous α-polymorphic eletriptanhydrobromide is complete. An optional annealing step (c), as describedabove, may also be carried out.

This process is particularly advantageous since previously the onlyviable large scale process for converting mixed polymorphic and/orsolvated/hydrated forms of eletriptan hydrobromide to the pureα-polymorph of eletriptan hydrobromide involved breaking the salt to thefree base as a preliminary step.

Eletriptan is preferably prepared according to Scheme 1 below.

Compound (II) ((R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole)may be prepared by the methods described in U.S. Pat. No. 5,607,951 orEP-B-1088817.

Compound (III)((R)-1-acetyl-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole) maybe prepared by treating a solution of compound (II) in acetonitrile,with acetic anhydride and triethylamine. The reaction is preferablycarried out under reflux.

Compound (IV)((R)-1-acetyl-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole)may be prepared by treating a solution of compound (III) in acetonitrilewith triethylamine, tri-o-tolylphosphine, palladium acetate andphenylvinylsulphone. The reaction is preferably carried out underreflux.

Conveniently, compound (II) may be converted to compound (IV) withoutisolation of compound (III).

Compound (V)((R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole)may be prepared by treating a solution of compound (IV) in methanol withpotassium carbonate. The reaction is preferably carried out at roomtemperature. A similar process, described in the prior art (see Example58 of U.S. Pat. No. 5,607,951) uses recrystallisation to purify andisolate compound (V). Recrystallisation is indeed an effective means ofpurification, particularly from a mixture of acetonitrile and water or amixture of acetone and water, but the yield of product obtained issub-optimal. Surprisingly, it has been found that column chromatographyis a more efficient method of purifying crude compound (V), even on alarge multikilogram scale, and a significantly higher yield of productcan be isolated in this way.

When chromatography is used to purify compound (V), the methanolicsolution resulting from the reaction is filtered and neutralised with anaqueous acid, preferably phosphoric acid. The mixture is then loadedonto a column packed with a suitable stationary phase (preferably astyrene polymer such as CG-161 resin, available from Tosoh Bioscience).The column is eluted with a mixture of acetone and an aqueous acid(preferably acetic or phosphoric acid) and the fractions containingproduct are combined and concentrated. Acetone is added to theconcentrated solution and the pH is adjusted to from 10 to 11 using asuitable base, such as potassium carbonate, to precipitate the product.The product is collected, washed with water and dried.

Compound (VI) (eletriptan) may be prepared by treating a solution ofcompound (V) in a mixture of acetone and water with palladium on carbonand methanesulphonic acid under an atmosphere of hydrogen. A catalystcomprising 5% palladium on carbon is preferred. A particularlyadvantageous catalyst for use in this process is PMC 2020C (supplied bythe Precious Metals Corporation), requiring a catalyst loading as low as7%.

The following Examples illustrate particular ways of putting theinvention into effect. Differential scanning calorimetry (DSC) wasperformed using a Perkin Elmer DSC-7 instrument. Approximately 10 mg ofeach sample was accurately weighed into a 50 microlitre aluminium pan.The samples were heated at 20° C./minute over the range 40° C. to 220°C. with a nitrogen gas purge.

EXAMPLE 1

(a) (R)-5-Bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole (256 kg),acetonitrile (380 kg), triethylamine (115 kg) and acetic anhydride (115kg) were charged to a dry glass lined vessel. The reaction mixture washeated to reflux and maintain at this temperature for 4.5 hours.

(b) A mixture of acetonitrile (375 kg), palladium acetate (12.5 kg) andtri-o-tolylphosphine (60 kg) was stirred for 1 hour. Phenyl vinylsulphone (160 kg), triethylamine (92 kg) and finally the solutionprepared in part (a) were added and the mixture was heated to reflux for7.5 hours. The reaction mixture was cooled and a solution of 190 kgconcentrated hydrochloric acid in 1200 kg water was added over 4 hours.The resulting mixture was filtered to remove spent catalyst and afurther 3000 kg of water and 300 kg of 50% w/w aqueous sodium hydroxidesolution were added to the filtrate to precipitate the product. Theresulting suspension was filtered and washed with water (500 kg) toyield crude(R)-1-acetyl-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole)as a dark brown, wet, crystalline solid (535 kg wet, equivalent of 338kg dry). This crude product was added to 530 kg of acetone and themixture was heated to 60° C. On reaching this temperature 814 kg ofwater was added over 2 hours whilst simultaneously cooling the mixtureback to ambient temperature. The batch was then granulated for 2 hoursand filtered to yield the purified product (350 kg wet, equivalent of280 kg dry, 83%).

EXAMPLE 2

Methanol (660 kg) and(R)-1-acetyl-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(77 kg dry equivalent of the recrystallised product of Example 1) werecharged to a vessel and the resulting mixture was stirred for 5 minutes.Potassium carbonate (8.9 kg) was added and the mixture was stirred atroom temperature for 30 minutes. The reaction mixture was then warmed to35° C. and Norit carbon (11.6 kg) and water (235 kg) were added. Theresulting mixture was filtered and the filtrate was diluted by theaddition of water (1300 kg, added over two hours) and granulated for 2hours at room temperature. Filtration gave crude(R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(75 kg wet, equivalent of 60.5 kg dry, 88%).

EXAMPLE 3

A mixture of acetonitrile (940 kg) and crude(R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(478 kg dry equivalent, product of the process of Example 2) was warmedto 55° C. Water (720 kg) was added and the mixture was cooled to 20° C.and granulated for 2 hours at that temperature. Pure(R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(482 kg wet, equivalent of 393 kg dry, 82%) was recovered by filtration.

EXAMPLE 4

Acetone (1140 kg) and(R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(482 kg dry equivalent, recrystallised product of Example 3) werecharged to a vessel and the mixture was warmed to 55° C. Water (1520 kg)was added and the mixture was cooled to 20° C. and granulated for 2hours. Recrystallised(R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(492 kg wet, 343 kg dry equivalent, 87%) was isolated by filtration.

EXAMPLE 5

(R)-5-(2-Phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole(200 kg dry equivalent) and acetone (1186.5 kg) were charged to a dry,glass lined vessel. De-ionised water (300 kg), further acetone (237 kg),methanesulphonic acid (55 kg) and a slurry of palladium on carbon (22.4kg dry equivalent) in de-ionised water (200 kg) were added and themixture was hydrogenated under an atmosphere of hydrogen gas. Thereaction slurry was filtered to remove the catalyst. De-ionised water(1300 kg) and 48% aqueous sodium hydroxide solution (60 kg) were addedto precipitate the product, which was isolated by filtration and washedwith a mix of de-ionised water (210 kg), acetone (83 kg) and furtherde-ionised water (710 kg) to yield3-{[1-methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indole(220 kg wet, 157.65 kg when dry, 78.41%).

EXAMPLE 6

3-{[1-Methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indole(15 kg) and 2-butanone (204 kg) were charged to a dry, glass-linedvessel. A solution of 48% aqueous hydrobromic acid (6.45 kg) in2-butanone (63 kg) was added and the resulting slurry was subjected toazeotropic distillation until a volume of 150 litres remained. Thereaction mixture was cooled to 17.5° C. and the product was isolated byfiltration. The product was washed with 2-butanone (16 kg) to yield theα-polymorphic form of3-{[1-Methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indolehydrobromide (18.2 kg wet,17.5 kg when dry, 96.3%). DSC: A single majorendotherm with a peak maximum in the range 173°-179° C. was observed,indicative of the α-polymorph (see WO-A-96/06842).

EXAMPLE 7

α-Polymorphic3-{[1-methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indolehydrobromide (300 kg) and toluene (3892 kg) were charged to a dry,glass-lined vessel. The resulting slurry was heated under reflux andapproximately 666 kg of toluene was removed by distillation. The slurrywas cooled to 100-105° C. and then a further 666 kg of toluene wasremoved by distillation. The reaction slurry was then cooled to 22.5° C.and the product was isolated by filtration. The product was washed withtoluene (908 kg) to yield α-polymorphic3-{[1-methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indolehydrobromide (289 kg dry weight, 96.3%). DSC: A single major endothermwith a peak maximum in the range 173°-179° C. was observed, indicativeof the α-polymorph (see WO-A-96/06842).

EXAMPLE 8

3-{[1-Methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indolehydrobromide (10 kg), 2-butanone (63 kg) and de-ionised water (0.65 kg)were charged to a dry, glass-lined vessel and heated to 67.5° C. to forma solution. The solution was then cooled to 60° C. and further2-butanone (42 kg) was added to precipitate the product. The resultingslurry was subjected to an azeotropic distillation to leave a finalreaction volume of 50 litres and then cooled to 22.5° C. The product wasisolated by filtration and washed with 2-butanone (10.5 kg) to yieldα-polymorphic3-{[1-methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indolehydrobromide (9.3 kg dry weight, 93%). DSC: A single major endothermwith a peak maximum in the range 173°-179° C. was observed, indicativeof the α-polymorph (see WO-A-96/06842).

COMPARATIVE EXAMPLE

3-{[1-Methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indole(274 kg) and acetone (3419 kg) were charged to a dry, glass-linedvessel. A solution of 48% aqueous hydrobromic acid (114.7 kg) in acetone(1383 kg) was added at a temperature of from 50 to 55° C. over 1 hourand the resulting slurry was stirred for 4 hours. The reaction mixturewas cooled to from 30 to 35° C. and the product was isolated byfiltration. The product was washed with acetone (861 kg) to yield theα-polymorphic form of3-{[1-methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indolehydrobromide (242.4 kg dry, 73.0%). DSC: A single major endotherm with apeak maximum in the range 173°-179° C. was observed, indicative of theα-polymorph see WO-A-96/06842).

1. A process for preparing α-polymorphic eletriptan hydrobromidecomprising the steps of (a) treating a solution of eletriptan in2-butanone with hydrobromic acid and (b) distilling off a2-butanone/water azeotrope until formation of anhydrous α-polymorphiceletriptan hydrobromide is complete.
 2. A process as claimed in claim 1wherein the water content of the reaction mixture is reduced to lessthan 0.5% weight/weight in step (b).
 3. A process as claimed in claim 1comprising the extra step of slurrying the product of step (b) inrefluxing toluene and removing a proportion of the toluene bydistillation.
 4. A process as claimed in claim 3 wherein at least 12% ofthe toluene is removed.
 5. A process as claimed in claim 1 wherein theeletriptan starting material is prepared by treating a solution of(R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolein acetone with palladium on carbon and methanesulphonic acid under anatmosphere of hydrogen.
 6. A process as claimed in claim 5 wherein the(R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoleis prepared by treating a solution of(R)-1-acetyl-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indolein methanol with potassium carbonate.
 7. A process as claimed in claim 6wherein the(R)-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoleis purified by column chromatography.
 8. A process as claimed in claim 6wherein the(R)-1-acetyl-5-(2-phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indoleis prepared by treating a solution of(R)-1-acetyl-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole inacetonitrile with triethylamine, tri-o-tolylphosphine, palladium acetateand phenylvinylsulphone.
 9. A process as claimed in claim 8 wherein the(R)-1-acetyl-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole isprepared by treating a solution of(R)-5-bromo-3-(N-methylpyrrolidine-2-ylmethyl)-1H-indole in acetonitrilewith acetic anhydride and triethylamine.
 10. A process for preparing acrystalline, α-polymorphic form of eletriptan hydrobromide from anyother polymorphic and/or solvated/hydrated form of eletriptanhydrobromide or from a mixture of different polymorphic and/orsolvated/hydrated forms, including a mixture comprising the α-polymericform itself, comprising (a) crystallising a solution of the eletriptanhydrobromide starting material in a mixture of 2-butanone and water and(b) distilling off a 2-butanone/water azeotrope until the formation ofanhydrous α-polymorphic eletriptan hydrobromide is complete.
 11. Aprocess as claimed in claim 10 comprising the extra step of slurryingthe product of step (b) in refluxing toluene and removing a proportionof the toluene by distillation.